Hallmarks of aging that have critical impact on health include weight gain and reduced physical fitness, usually starting at middle age. These changes lead to insulin resistance and development of many diseases including type-2 diabetes. The molecular events that drive the metabolic and fitness decline in older age are poorly understood. We discovered that DNA-dependent protein kinase (DNA-PK) is a mediator of the aging-associated decline in metabolism and fitness. Aging increases DNA-PK activity, decreasing the ability of HSP90 to chaperone clients such as AMP-activated protein kinase (AMPK). Inhibiting DNA-PK either genetically or with a small molecule inhibitor prevents the weight gain, decline of mitochondrial function and physical fitness in middle age mice and protects against type-2 diabetes in obese mice. We conclude that DNA-PK activates a metabolic brake at older age, which makes staying lean and physically fit difficult at older age and increases susceptibility to metabolic diseases.